Acquired abdominal aortic aneurysms are usually associated with a mural thrombus through which blood continues to flow. Some early data suggest that aneurysmal evolution correlates with the biological activity of the thrombus. Our hypothesis was therefore that the thrombus could adsorb blood components and store, release, and participate in the activation of proteases involved in aneurysmal evolution. For this purpose, we have explored both the metalloproteinase and fibrinolytic systems in the thrombus and the wall of human aneurysms. We have first investigated blood clot formation and lysis in vitro. Spontaneous clotting induces a release of promatrix metalloproteinase (pro-MMP)-9 into the serum that was fourfold higher than in paired control plasma (P < 0.001). Fibrinolysis progressively released more MMP-9 in a time-dependent manner (P < 0.01). After selective isolation, we demonstrated that polymorphonuclear leukocytes are the main source of MMP-9 release during clot formation. Protease content was then analyzed in 35 mural thrombi and walls of human abdominal aortic aneurysms sampled during surgical repair. In 15 aneurysms, the liquid phase at the interface between the thrombus and the wall was sampled separately. Both thrombus and wall contained MMP-2 and MMP-9 but the ratio MMP-9/MMP-2 was higher in the thrombus than in the wall. The liquid interface also contained active MMP-9. Immunohistochemistry of the thrombus confirmed these findings, showing the presence of polymorphonuclear leukocytes at the luminal pole of the thrombus, co-localizing with MMP-9 storage. In contrast, MMP-3 and MMP-7 were only present in the aneurysmal wall. Plasminogen was present in the mural thrombus but plasmin activity was present in both thrombus and wall. In the liquid interface, plasmin-alpha(2)-anti-plasmin complexes were detected demonstrating in vivo the activation of plasminogen. In contrast, u-PA and t-PA were detectable only in the wall, suggesting that plasminogen present in the thrombus could be activated by factors secreted by the arterial wall. This was demonstrated in vitro, in which co-incubation of thrombus and wall extracts generated plasmin in the presence of a fibrin matrix and activated MMPs. In conclusion, our study strongly suggests that the mural thrombus, by trapping polymorphonuclear leukocytes and adsorbing plasma components could act as a source of proteases in aneurysms that may play a critical role in enlargement and rupture.

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Hemodynamic overload of the atria is an important pathogenic factor of fibrosis; MMP-7 appears to be involved in the early stage of this tissue remodeling process.

Background: Age-related arterial alterations affecting cells, matrix and biomolecules are the main culprit for initiation and progression of cardiovascular disease. The objective of this study is to gain further insights into the complex mechanism of elastic tissue ageing in human aortic blood vessels. Methods: One hundred and nineteen human aortic tissue samples were collected from adult patients (101 males, 18 females; age 40–86 years) undergoing coronary artery bypass grafting. Overall extracellular matrix architecture was examined by multiphoton laser scanning microscopy and histology. Matrix metalloproteinases 2 and 9, corresponding tissue inhibitors 1 and 2 as well as desmosine were determined. mRNA levels of tropoelastin were assessed by quantitative RT-PCR. Results: Age-related destruction of the vascular elastic laminas as well as a loss of interlamina cross-links were observed by laser scanning microscopy. These results were confirmed by histology indicating increasing interlamina gaps. There were no significant differences in matrix turnover or desmosine content. A steady decrease in tropoelastin mRNA by about 50% per 10 years of age increase was observed. Conclusions: Our findings indicate that ageing is accompanied by a destruction of the elastic vascular structure. However, tropoelastin expression analysis suggests that elastogenesis occurs throughout life with constantly decreasing levels.

Elastin peptides are present in human blood. As elastin receptors exist on several cell types, especially endothelial cells, this investigation was carried out to study the effect of elastin peptides on vascular tone. For this purpose, rat aortic rings were mounted in an organ bath for isometric tension measurements. Elastin peptides (ĸ-elastin) were added in the concentration range of 0.1 ng/ml to 1 µg/ml, concentrations similar to those found in the circulating blood. In rat aortic rings, precontracted or not with noradrenaline (10^–6M), elastin peptides induced an endothelium-dependent vasodilation. The pretreatment of aortic rings with N-ω-nitro-L-arginine methyl ester (10^–5M), an inhibitor of nitric oxide (NO) production, or with indomethacin (10^–5M), an inhibitor of cyclooxygenase, prevented elastin peptide-induced vasodilation. These findings suggest that elastin peptides act through the synthesis of prostanoids, leading to the production of NO. Moreover, this relaxant effect of elastin peptides was decreased or inhibited when aortic rings were treated with lactose (10^–5 to 10^–2M) or laminin (10^–6 to 10^–4 mg/ml) whereas lactose or laminin was unable to inhibit acetylcholine-induced vasodilation. These findings suggest that the inhibitory effects of lactose and laminin are specific for elastin peptide receptors and are in agreement with previous studies on these receptors. As there is evidence of the degradation of elastin in several vascular diseases, the concept that elastin peptides may contribute to the control of vascular tone is discussed.

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Abstract-The elastin content in the thoracic aorta of male Brown-Norway (BN) rats is 31.4Ϯ1.2% (dry weight), whereas that of male LOU rats is 37.2Ϯ1.0%. A similar difference in the elastin content of the thoracic aorta is also observed in female animals. Furthermore, in the thoracic aorta of young, growing rats as well as in cultured aortic smooth muscle cells, the steady-state level of elastin mRNA is significantly lower in the BN than in the LOU strain. These results suggested that 1 or more genes control the elastin mRNA level and the elastin content in the aortas of BN and LOU rats.A possible relationship between a polymorphism in the elastin gene and the elastin content of the aorta was tested. For this purpose, the aortic elastin content was measured in F 1 and F 2 generations bred from LOU and BN rats and was compared with that of the F 0 (parental) generation. A polymorphic marker located in intron 25 of the elastin gene has been used to genotype the F 2 rats. The degree of genetic determination of aortic elastin content was estimated to be 73% in the F 2 cohort, but the elastin locus accounts for only 3.9% of the total variance in aortic elastin content. Other genes are thus responsible for the major part of the observed interstrain difference by regulating the transcription of the gene, the stability of elastin mRNA, and/or posttranslational events. (Arterioscler Thromb Vasc Biol. 1999;19:2308-2315.)Key Words: elastin Ⅲ genetics Ⅲ aorta Ⅲ rats T he deposition of functional elastic fibers in arteries during development and growth is a complex process with the possibility of regulation at many levels. Synthesis of tropoelastin and glycoprotein molecules is followed by the relevant organization of these molecules in the extracellular space and the subsequent formation of cross-links between tropoelastin molecules. 1,2 Tropoelastin synthesis is the result of the expression of 1 gene and appears to be subjected to complex regulatory processes. Developmental regulation of elastin gene expression results in careful control of the chronology of elastin synthesis during embryonic and postnatal growth, which is also tissue and site specific. [3][4][5][6] The mechanisms of this regulation are not yet fully understood. Many factors have been shown to regulate elastin synthesis, such as mechanical factors, cytokines, growth factors, hormones, pharmacological agents, and the composition of the extracellular matrix. [3][4][5][6] In essentially all of the in vitro and in vivo studies, changes in elastin synthesis have been shown to be correlated with changes in steady-state elastin mRNA (mRNA E ) levels.Study of the possible genetic control of elastin synthesis had not been previously attempted because no suitable animal model was available. Recent studies on knockout mice have shown that complete deletion of the elastin gene results in obstructive arterial disease, which leads to death 4 days after birth. 7 In addition, the elastin gene is implicated in human arterial pathology, since patients with supravalvular aort...